Therapeutic Potential of Mesenchymal Stem Cells in a Pre-Clinical Model of Diabetic Kidney Disease and Obesity.
Christian Sávio-SilvaPoliana E Soinski-SousaAntônio Simplício-FilhoRosana M C BastosStephany BeyerstedtÉrika Bevillaqua RangelPublished in: International journal of molecular sciences (2021)
Diabetic kidney disease (DKD) is a worldwide microvascular complication of type 2 diabetes mellitus (T2DM). From several pathological mechanisms involved in T2DM-DKD, we focused on mitochondria damage induced by hyperglycemia-driven reactive species oxygen (ROS) accumulation and verified whether mesenchymal stem cells (MSCs) anti-oxidative, anti-apoptotic, autophagy modulation, and pro-mitochondria homeostasis therapeutic potential curtailed T2DM-DKD progression. For that purpose, we grew immortalized glomerular mesangial cells (GMCs) in hyper glucose media containing hydrogen peroxide. MSCs prevented these cells from apoptosis-induced cell death, ROS accumulation, and mitochondria membrane potential impairment. Additionally, MSCs recovered GMCs' biogenesis and mitophagy-related gene expression that were downregulated by stress media. In BTBRob/ob mice, a robust model of T2DM-DKD and obesity, MSC therapy (1 × 106 cells, two doses 4-weeks apart, intra-peritoneal route) led to functional and structural kidney improvement in a time-dependent manner. Therefore, MSC-treated animals exhibited lower levels of urinary albumin-to-creatinine ratio, less mesangial expansion, higher number of podocytes, up-regulation of mitochondria-related survival genes, a decrease in autophagy hyper-activation, and a potential decrease in cleaved-caspase 3 expression. Collectively, these novel findings have important implications for the advancement of cell therapy and provide insights into cellular and molecular mechanisms of MSC-based therapy in T2DM-DKD setting.
Keyphrases
- cell death
- cell cycle arrest
- mesenchymal stem cells
- cell therapy
- high glucose
- umbilical cord
- hydrogen peroxide
- type diabetes
- gene expression
- diabetic nephropathy
- endothelial cells
- high fat diet induced
- glycemic control
- metabolic syndrome
- bone marrow
- insulin resistance
- weight loss
- induced apoptosis
- stem cells
- endoplasmic reticulum stress
- weight gain
- dna methylation
- adipose tissue
- risk assessment
- blood pressure
- oxidative stress
- reactive oxygen species
- diabetic rats
- uric acid
- dna damage
- wound healing
- gestational age
- anti inflammatory
- transcription factor
- physical activity
- newly diagnosed
- replacement therapy
- stress induced
- climate change
- heat stress